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Diagnosis of myeloma related disorders
Dr. Paul Mellor, DECVIM
Complete investigations for myeloma related disorders are complex and may take several days. Ideally, referral to a multi-disciplinary specialist centre is in the best interests of the patient. Work-up may include:
Diagnosis should be based on accurate histopathological / cytological classification & immunolabelling preferably alongside the demonstration of a paraproteinaemia where relevant / possible. In our series, the histopathological diagnosis was given primacy over the cytological diagnosis on the basis that exams of repeat sections of tissue were more likely to be representative than cytological slides alone. The confidence in a cytological diagnosis will be enhanced with either immunocytochemistry and/or concurrent tissue biopsy. A cytological / histopathological diagnosis of lymphoma is allowed as an MRD, so long as there is a paraproteinaemia as evidenced by eg serum protein electrophoresis.
Defining plasma cells, plasma cell pathology including MRDs
What are plasma cells ? To answer this, an understanding of normal B cell development is necessary. The normal physiological development of the mammalian B lymphocyte commences in the bone marrow. Here, the pre-B cell undergoes re-arrangement of its heavy- and light- chain immunoglobulin (IgH and IgL) genes resulting in the expression of surface IgM. Upon further maturation, the naïve B lymphocyte migrates to secondary lymphoid tissues where stimulation with antigen and the provision of T cell help leads to its proliferation and differentiation into plasmablasts. These form either IgM secreting plasma cells, many (but not all) of which have a short lifespan in the periphery, or they enter lymphoid follicular centres. In lymph node or splenic germinal centres, the plasmablasts undergo active somatic hypermutation of the IgH and IgL gene sequences resulting in an antigen-selected clone that expresses high affinity immunoglobulin. Some are released into blood as lymphoplasmacyte memory cells, whereas others switch immunoglobulin isotype from IgM to IgG, IgA or IgE. The full morphological and functional transition to a terminally-differentiated plasma cell occurs after exiting the germinal centre and appears to be associated with migration into new microenvironments. In man, the principal site is the bone marrow, but studies in rodents have identified five other key sites: splenic red pulp, lymph node medullary cords, gastro-intestinal tract, respiratory tract and inflamed tissues (Potter 2003, Seidl et al 2003). What are myeloma cells ? Myeloma cells are neoplastically transformed plasma cells. From cytogenetic and molecular studies in human myeloma patients and mouse myeloma models, a multi-step model of the evolution of myeloma has been hypothesized. An early event is chromosomal translocation in the immunoglobulin heavy chain site, leading to the immortalization of a plasma cell clone. A potential clinical manifestation of this event is monoclonal gammopathy of unknown significance (MGUS). The condition is denoted by the presence of a serum monoclonal protein (M-protein or paraprotein) in the absence of significant infiltration of the bone marrow or extramedullary tissues by plasma cells. This is a well recognized disorder in man that is clinically associated with an increased risk of developing multiple myeloma (Kyle 1993). Molecular studies have confirmed that further chromosomal changes, including deletions of genes and / or activation of oncogenes, allows the creation of a neoplastic plasma cell (Seidl et al 2003). Recent work has suggested that myeloma cells are derived from a stem cell tumourogenic clone (Matsui et al 2004).
Myeloma (neoplastic plasma cells) can be differentiated from normal plasma cells and other non-cancerous plasma cell lesions (e.g. reactive plasma cell lesions in a variety of tissues including lymphocytic-plasmacytic stomatitis, lymphocytic-plasmacytic dermatopathies and plasma cell granulomas) with the aid of cytology, histopathology and more specifically by immuno-labeling (as a surrogate indicator of monoclonality), cytogenetic and molecular studies.
MRD include the following:
1) Multiple Myeloma
2) Extramedullary plasmacytoma (EMP)
In human and canine CEMP, the disease is usually unaccompanied by systemic clinical signs, typicially follows a benign course and excision is curative (Clark et al 1992, Soutar et al 2004). Occasional feline CEMP cases follow a similar course (Mellor et al 2006). However in feline CEMP, the majority of reported cases had a paraproteinaemia; suffered rapid tumour development and had evidence of multi-organ and bone marrow myeloma cell infiltration (Dust et al 1982, Harbison 1987, Carothers et al 1989, Radhakrishnan et al 2004, Mellor et al 2006).
All reported NCEMP feline cases have had signs of systemic disease attributable to a paraproteinaemia and / or metastatic behaviour (Williams and Goldschmidt 1982, Harbison 1987, Mandel and Esplin 1994, Ward et al 1997, Zikes et al 1998, Michau et al 2003, Mellor et al 2006). Typically, the liver and/or spleen were infiltrated. Other locations have included the kidneys, gastro-intestinal tract, lymph nodes, stomach, epidura, orbit, iris and retroperitoneal space.
3) Solitary plasmacytoma of bone (SPB)
4) Waldenström (IgM) macroglobulinemia
5) Immunoglobulin secreting lymphoma
6) Myeloma cell leukaemia
Notes on hyperglobulinaemia and paraproteinaemia
MGUS has been reported in the cat, although the level of detailed case investigation has varied - so it is not always possible to determine whether EMP, or other MRD, or non-neoplastic conditions were absolutely excluded (MacEwen and Hurvitz 1977, Patel et al 2005). MGUS have been reported in a number of non-neoplastic conditions in the dog (leishmaniasis, ehrlichiosis, chronic pyoderma) (Burkhard et al 1995, Giraudel et al 2002). This is not an area that is well reported in the cat at this time. In the cat, there are poorly described possible cases of FIP in association with a monoclonal gammopathy (MacEwen and Hurvitz 1977, Hanna 2005). Immunohistochemical demonstration of single Ig light chain expression was not reported in these cases.
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Date Published: May 21, 2007 Paul Mellor ©
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